The Crises of the Newborn Norepinephrine is Still a Necessity

Rescued TH-null mutants and the few that survive birth without supplementation are born with normal weight, length, appearance, and blood glucose levels. However they've no sooner survived the hypoxic crises of their life in utero, but they encounter a new crisis: life ex utero. The untreated TH-null pups, at first indistinguishable from their littermates, live days to weeks but not beyond weaning unless they are specially treated.

Life of the newborn is similar to that of the fetus in that norepinephrine is the single essential catecholamine for life between birth and weaning. Fetuses appear to have a single problem that norepinephrine conquers; that is avoiding hypoxia. Newborns, on the other hand, are confronted with a multitude of problems if they are born without norepinephrine. Eating is not one of these. Newborns have no need for dopamine for motivation to eat. Like the fetuses, the heart rate of the neonatal pups is abnormally slow. They would not be able to mount a "fight or flight" response but their laboratory-bound life style does not permit such emergencies.

The TH-null mutants are so very hungry; they suck avidly and their mothers take good care of them. However, in spite of stomachs full of milk throughout their lives, the mutants fail to thrive. Mutant neonates do not gain weight after their second or third day; they weigh between 3 and 4 grams throughout their lives. The TH-nulls maintain the weight of a normal 4 day-old pup which would be expected to weigh between 8 and 10 grams at two weeks of age. The mutants are deficient in length, crown to tail, as if they had been starved (Figure 1). But unlike unfed normal pups with equivalent weight and length, the TH-null mutants become severely hypoglycemic though they always have milk in their stomachs and their livers store glycogen. The TH-null mutants display normal insulin responses though they do not experience the normal rise in blood insulin levels that occur with age. After a glucose challenge, blood glucose levels rise to the levels that are produced in controls after the same challenge. After a glucose challenge, the controls return to the pre-challenge glucose levels and so do the mutants. The mutants return to the same low glucose values as before the challenge. These low values apparently are sensed by the TH-nulls as normal glucose levels. That the TH-null mutants respond to glucose normally shows that the pancreas has developed in that it secretes insulin in response to glucose.

Figure 1. Black mice and white mice. TH-null mutants with wild-type littermates on postnatal day 18. The pair on the left are on a C57Bl6 background. The mutant makes small amount of catecholamines in spite of lack of tyrosine hydroxylase. The pair on the right lack pigment because they carry a mutation that disables the gene that codes for tyrosinase in the melanin pathway. The small white mouse lacks both tyrosine hydroxylase and tyrosinase.

Figure 1. Black mice and white mice. TH-null mutants with wild-type littermates on postnatal day 18. The pair on the left are on a C57Bl6 background. The mutant makes small amount of catecholamines in spite of lack of tyrosine hydroxylase. The pair on the right lack pigment because they carry a mutation that disables the gene that codes for tyrosinase in the melanin pathway. The small white mouse lacks both tyrosine hydroxylase and tyrosinase.

The failure-to-grow phenotype of mice that lack catecholamines is illustrated in Figure 1, which pictures two TH-null pups and two wild-type mice. One pair is black, on a C57 Bl /6J background and the other is albino. The albino mice were created after the pigmented heterozygous carriers were backcrossed onto albino CD1 mice. The albino pair are homozygous tyrosinase-deficient due to a naturally occurring mutation in the gene that codes for tyrosinase. In this way we created mice that lack activity of both TH and tyrosinase [5]. Each pair of pups pictured were 18 day-old littermates produced by heterozygote carriers of the TH-null mutation. At this age, the weight disparity between normal and mutant is very great: TH-null pups weigh only about one-third of their littermates. The mutant pups fail to grow length as well. There are no such differences between the wild-type and the TH-null heterozygote which indicates that a single copy of TH produces sufficient catecholamine and in fact we've noted that the heterozygotes production of catecholamine is equivalent to that of the wild-type.

The TH-null pups are developmentally behind their normal littermates as well as being very small. For example, eye opening in normal mice occurs by postnatal day 14, the eyes of TH-null mutants remain closed at least a week longer than is normal.

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